Parkinson's disease is a progressive, neurodegenerative disorder caused by a loss of the cell bodies of dopaminergic (DA-ergic) neurons from the substantia nigra and degeneration of nerve terminals in the striatum resulting in low levels of DA in the substantia nigra and corpus striatum. Parkinson's disease is characterized by chronic, progressive motor dysfunction and its main symptoms are tremor at rest, muscle rigidity and a decrease in the frequency of voluntary movements (hypokinesia) with difficulty in stopping, starting and turning when walking. A persistent tremor is superimposed on hypertonicity of opposing muscle groups and initiation of movements becomes increasingly difficult and slow. In advanced stages, patients' movements become virtually “frozen”, and patients are unable to care for themselves. Studies have shown that the symptoms of Parkinson's disease appear when the striatal DA content is reduced to 20–40% of normal.
As Parkinson's disease is associated with a loss of DA from the striatum, it is commonly treated with drugs which replace DA, the most commonly used of these being levodopa. Levodopa is converted by dopa decarboxylase into DA in the brain and it is this DA which exerts a therapeutic effect. However, although levodopa is well absorbed from the small intestine, much of it is inactivated by monoamine oxidase in the wall of the intestine. Also, the plasma half-life of levodopa is short and about 95% of the drug is converted to DA in pripheral tissues, where dopa decarboxylase is widespread, with the result that less than 1% enters the brain. Consequently levodopa has to be administered in large and frequent doses. In addition, the production of DA in peripheral tissues gives rise to unwanted side-effects.
Accordingly, levodopa is normally given in combination with other drugs to enhance the effects of levodopa in the brain and minimize its peripheral effects. In particular, levodopa is usually given in combination with a peripheral dopadecarboxylase inhibitor, which cannot cross the blood-brain barrier, such as carbidopa, which inhibits the breakdown of levodopa to DA outside the brain, thereby reducing peripheral unwanted effects. The inhibitor also ensures that a relatively large amount of an oral dose of levodopa reaches the brain and thus enables the dose of levodopa to be reduced which also reduces peripheral side-effects. In addition, a peripheral DA antagonist, which does not penetrate the blood-brain barrier, such as domperidone, may also be administered to reduce the nausea and vomiting side-effects of levodopa.
In addition to the side-effects mentioned above, further undesirable effects are associated with the prolonged use of levodopa. In particular, many patients develop involuntary choreiform movements, which are the result of excessive activation of DA receptors. These movements usually affect the face and limbs and can become very severe. Such movements disappear if the dose of levodopa is reduced but this causes rigidity to return. Moreover, the margin between the beneficial and the unwanted effect appears to become progressively narrower as the period of levodopa treatment increases. The traditional method of combating this effect is to increase the frequency of administration of levodopa whilst keeping the overall dose steady. This approach reduces end-of-dose deterioration and diminishes the likelihood of the patient developing the dyskinesias that occur with high peak doses.
A further complication of long-term levodopa treatment is the development, of rapid fluctuations in clinical state where the patient switches suddenly between mobility and immobility for periods ranging from a few minutes to a few hours. This phenomenon is known as the “on-off effect”, the “on” state being the preferred state during which nearly normal motor functioning can be attained and the “off” state being characterized by dystonic postures during periods of decreased mobility. Indeed, this effect can produce such an abrupt loss of mobility that the patient may suddenly stop while walking or be unable to rise from a chair in which he had sat down normally a few moments earlier. This effect is commonly unaffected by manipulation of the dose of levodopa and may require treatment with alternative drugs. In addition to the above long-term side-effects of levodopa treatment, it has been found that the effectiveness of levodopa gradually declines with time until it is no longer effective. Also, an increased incidence of malignant melanoma has been observed in patients undergoing treatment with levodopa and it has therefore been suggested that treatment with levodopa may be linked with the development of malignant melanoma. Accordingly, the use of levodopa in the treatment of Parkinson's disease is far from ideal.
An alternative approach to the treatment of Parkinson's disease is the use of drugs that mimic the action of DA. Such drugs are collectively known as DA agonists because they directly stimulate DA receptors within the DA-deficient nigrostriatal pathway. Unlike levodopa, DA agonists do not need to be converted in the brain to active compounds. Also, DA agonists are effective in patients in the advanced stages of Parkinson's disease when levodopa is no longer effective because they act directly on the DA receptors and are therefore unaffected by the lack of DA-producing nerve cells in such patients. However, the action of such DA agonists on the DA receptors also causes unwanted DA-ergic effects, such as nausea, vomiting and extrapyramidal effects, which can be debilitating and some DA agonists, such as apomorphine, are associated with further undesirable side-effects, especially when high doses are used, such as sedation, respiratory depression, hypotension, bradycardia, sweating and yawning. The severity and nature of such side-effects can be affected by the mode of administration of the drug. For instance, studies involving apomorphine have investigated a variety of routes for administration of this drug. However, oral administration of apomorphine tablets has required high doses to achieve the necessary therapeutic effect, because apomorphine administered by this route undergoes extensive presystemic metabolism in the small intestine and/or liver (the first pass effect). Also, long-term studies involving such oral forms were stopped after 7–10 days due to unexplained rises in blood urea nitrogen. Sub-lingual administration of apomorphine tablets caused severe stomatitis on prolonged use with buccal mucosal ulceration in half the patients treated. Intranasal administration produced transient nasal blockage, burning sensation and swollen nose and lips and, in some of the patients tested, had to be withdrawn because of what was considered to be chemical inflammation of the nasal mucosa.1 
Accordingly, the only satisfactory way of administering apomorphine, which avoids high first pass metabolism, has been found to be subcutaneous administration and, thus, the only commercially available formulation of apomorphine is a liquid for subcutaneous injection or subcutaneous infusion. Even so, subcutaneous administration does not avoid the normal DA agonist side-effects, such as nausea and vomiting and subcutaneous administration, whether by injection or infusion, is not easy to accomplish, particularly by patients whose motor functions are already impaired, and therefore requires training of patients and caretakers. Also, the injection site must be changed every 12 hours to minimize risks of skin discoloration and nodules forming. In view of these problems, it is not surprising that the use of DA agonists, such as apomorphine, in the treatment of Parkinson's disease has been largely confined to the treatment of “off” periods caused by levodopa therapy despite the obvious clinical benefits of such drugs over levodopa.
It is apparent from the above that it would be highly desirable from a clinical point of view to find a way of administering DA agonists, such as apomorphine, which is easy for the patient to accomplish, therefore, reducing the need for supervision of administration and which bypasses first pass metabolism in the liver. In addition, such a formulation of apomorphine or of apomorphine prodrugs should have a more beneficial pharmacokinetic profile than apomorphine itself.2-5 
Aporphine pro-drugs have been described and tested in animal models in the past.6-21 Such pro-drugs have been mostly ester pro-drugs and di-symmetric, i.e. 10,11-di-esters. Thus, for instance, the following di-esters of aporphines have been described: di-acetyl, di-propionyl, dibutyryl, di-iso-butyryl, di-pivaloyl, di-pentanoyl, di-hexanoyl, di-hexadecanoyl, di-phenylacetyl, di-methoxyacetyl, di-trifluoroacetyl and di-heptafluorobutanoyl esters. Some reports of improved bioavailability of such esters have been presented, but the overall result was disappointing. As an example, the di-pivaloyl ester pro-drug was much less active than the parent compound apomorphine itself. Due to the steric character of the pivaloyl group, it may be speculated that the ester hydrolysis of such a bulky group may be slower than for e.g. an acetyl group. 10,11-Di-acetyl-apomorphine is almost as potent as apomorphine itself.6 
The possibility of preparing asymmetrical di-esters have been mentioned in U.S. Pat. No. 4,080,456.11 Such asymmetrical di-esters were, however, not disclosed by means of specific working examples illustrating their preparation and characteristics and it was conceived by the inventors of that publication that such asymmetrical di-esters are difficult to make and that the pharmacology of such di-esters may be difficult to predict. Thus, all known di-acyl-aporphines actually prepared in practice are symmetrically substituted, i.e. the same substituent is found on both the 10- and the 11-position of the aporphine skeleton. This is, of course, limiting with respect to optimalization of the physicochemical properties that are likely to be of importance for both transdermal and subcutaneous or intramuscular administration.